DESCRIPTION: The goal of this project is to understand how HIV-1 in neutralized by antibodies to its envelope glycoproteins and how primary viruses resist these antibodies. Understanding the neutralizing antibody response to HIV-1 infection is relevant to a full comprehension of viral pathogenesis, and is of particular importance to the rational development of HIV-1 vaccines based, at least in part, on the induction of humoral immunity. In principle, the binding of neutralizing antibodies to HIV virions will reduce their infectivity for CD4+ target cells. However, despite an extremely vigorous antibody response to its envelope glycoproteins, HIV neutralization titers during natural infection are generally weak. Furthermore, no experimental vaccine has yet induced strong, cross-neutralizing antibodies active against primary viruses. We believe that resistance mechanisms evolved by HIV-1 to counter neutralizing antibodies contribute significantly to this problem. During the first four years of this grant, the PI's group helped to characterize and understand these resistance mechanisms. To continue and extend this work he proposed in the 1st Specific Aim to refine and use novel assays of HIV-1 INTERACTIONS WITH cd4+ target cells, and to determine how inhibition of virus binding correlates with neutralization of infectivity. The role of the co-receptors CCR5 and CXCR4 in the neutralization of HIV-1 binding and entry will also be studied. In the second specific aim, he will asses the influence of viral phenotype (co-receptor usage) on the sensitivity of primary HIV-1 isolates to neutralizing antibodies. His third aim is to develop new assays for HIV-1 neutralization based on co-receptor transfected cells engineered to express reporter genes such as beta- galactosidase, luciferase and green fluorescent protein, then to use these assays to re-assess the capacity of serum antibodies to neutralize HIV-1.